Spermine oxidase promotes oxidative stress during islet inflammation.

Diabetes is characterized by impaired glucose homeostasis resulting from dysfunction and loss of insulin-producing islet β cells, with oxidative stress emerging as a contributor to β-cell injury. The polyamines (putrescine, spermidine, spermine) regulate cellular stress responses, and their metabolism can generate reactive oxygen species (ROS) and reactive aldehydes via catabolic enzymes such as spermine oxidase (Smox) and polyamine oxidase (Paox). Transcriptomic analyses of mouse and human islets exposed to proinflammatory cytokines revealed induction of the gene encoding Smox but no change in the gene encoding Paox, suggesting a role for Smox in amplifying inflammation-associated stress in islets. In developing zebrafish, the smox gene is expressed in the pancreas and enriched within endocrine cells. Using a β-cell-specific ROS-inducible zebrafish model, smox gene knockdown reduced intra-islet ROS and macrophage recruitment. Metabolomics of zebrafish embryos showed that Smox deficiency did not affect spermine or spermidine levels but led to accumulation of acetylated polyamines, consistent with the rerouting of polyamine flux through alternative acetylation pathways. RNA sequencing of zebrafish embryos demonstrated that Smox deficiency induces distinct transcriptional programs, with enrichment of cell cycle and RNA processing pathways at baseline and reprogramming of stress, translational, and immune-associated pathways during injury. Mechanistically, Smox is the primary polyamine pathway generating ROS in zebrafish, as reducing flux through the Paox-dependent pathway did not reduce ROS production. These findings support a model in which Smox amplifies β-cell stress through peroxide- and aldehyde-mediated toxicity and identify polyamine catabolism as a modifiable pathway in the setting of β-cell injury.